Roger Echols

Safety and Efficacy of Gatifloxacin Therapy for Children with Recurrent Acute Otitis Media (AOM) and/or AOM Treatment Failure

BACKGROUNDnBecause of concerns about arthrotoxicity, fluoroquinolones are restricted for use in children. This study describes the safety and efficacy of gatifloxacin when used for treatment of children with recurrent acute otitis media (ROM) or acute otitis media (AOM) treatment failure (AOMTF).nnnMETHODSnWe performed an analysis of 867 children included in 4 clinical trials who had ROM and/or AOMTF and were treated with gatifloxacin (10 mg/kg once daily for 10 days).nnnRESULTSnGatifloxacin had adverse event rates that were similar overall to those of a comparator antibiotic (amoxicillin-clavulanate), except for increased diarrhea in children <2 years old receiving amoxicillin-clavulanate. There was no evidence of arthrotoxicity, hepatotoxicity, alteration of glucose homeostasis, or central nervous system toxicity acutely or during 1 year follow-up in any child. Regarding efficacy, in 2 noncomparative trials, the gatifloxacin cure rate of AOM was 89% (95% confidence interval [CI], 83%-95%) at the test of cure (TOC) visit, 3-10 days after completion of therapy. In 2 comparative trials of gatifloxacin versus amoxicillin-clavulanate, the efficacy of gatifloxacin was 88% (95% CI, 82%-94%). Gatifloxacin led to better clinical outcomes than amoxicillin-clavulanate for AOMTF (91% vs. 81%; P=.029), for AOMTF and age <2 years old (89% vs. 69%; P=.009), and for severe AOM in children <2 years old (90% vs. 75%; P=.012). Among children with AOMTF previously treated with amoxicillin-clavulanate or ceftriaxone injections, gatifloxacin cure rates were high (88% and 75%, respectively).nnnCONCLUSIONSnGatifloxacin appears to be safe for children, with no evidence of producing arthrotoxicity in 867 children exposed to the antibiotic when used as treatment for ROM and AOMTF.

Developing Outcomes Assessments as Endpoints for Registrational Clinical Trials of Antibacterial Drugs: 2015 Update From the Biomarkers Consortium of the Foundation for the National Institutes of Health

One important component in determining the benefits and harms of medical interventions is the use of well-defined and reliable outcome assessments as endpoints in clinical trials. Improving endpoints can better define patient benefits, allowing more accurate assessment of drug efficacy and more informed benefit-vs-risk decisions; another potential plus is facilitating efficient trial design. Since our first report in 2012, 2 Foundation for the National Institutes of Health Biomarkers Consortium Project Teams have continued to develop outcome assessments for potential uses as endpoints in registrational clinical trials of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. In addition, the teams have initiated similar work in the indications of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. This report provides an update on progress to date in these 4 diseases.

Progress in the Fight Against Multidrug-Resistant Bacteria 2005–2016: Modern Noninferiority Trial Designs Enable Antibiotic Development in Advance of Epidemic Bacterial Resistance

Summary From a public health perspective, new antibacterial agents should be developed before widespread resistance to existing agents emerges. Anticipatory drug development based on noninferiority trials offers a path to making safe and efficacious antibiotics available ahead of epidemic resistance.

Good Correlation of Cefiderocol Between In Vivo Efficacy Murine Thigh/Lung Infection Models and MIC Determined in Iron-Depleted Conditions

Abstract Background Cefiderocol (S-649266) is a novel siderophore cephalosporin active against a wide variety of carbapenem-resistant Gram-negative bacteria such as Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia. This potent activity is mainly due to its efficient penetration through the outer membrane via active iron transporter systems and its high stability to both serine- and metallo-carbapenemases. The antibacterial activity is evaluated under iron-deficient conditions to mimic the infection sites in human. In this study, the efficacy in murine infection models was evaluated in order to show that the MIC under iron-deficient conditions is more predictive for the in vivo efficacy. Methods A total of 19 strains of E. coli, K. pneumoniae, P. aeruginosa and A. baumannii were used for the in vivo efficacy studies using neutropenic murine thigh or lung infection models. The efficacy was evaluated by the bacterial reduction at 24 hours after treatment by subcutaneous q3h administration of cefiderocol which was initiated at 2 hours post-infection. MIC of cefiderocol was determined by broth microdilution methods according to CLSI instruction using both CAMHB and iron-depleted CAMHB (ID-CAMHB). The PK/PD analysis was conducted by calculating the percentage T>MIC value of free plasma concentrations (fT>MIC) in infected mice. Results The efficacy in murine thigh and lung infection models were evaluated by using 12 and 15 strains, respectively. The average fT>MIC value required for static effect and 1 log10 reduction was shown to be 75% and 85%, respectively irrespective of Gram-negative bacterial species and the infection sites. The PK/PD analysis for 3 strains, which had large different MIC between two conditions (16, 2 and 2 mg/mL in ID-CAMHB and 128, 32 and 32 mg/mL in CAMHB, respectively) showed that the fT>MIC required for 1 log10 reduction ranged from 71.7% to 89.0% using the MIC in ID-CAMHB. On the other hand, these values were significantly lower (ranging from 10 to 50%) using the MIC in CAMHB. Conclusion The PK/PD analysis using murine thigh/lung infection models showed that ID-CAMHB is the appropriate media for MIC determination for the prediction of in vivo efficacy irrespective of infection sites and bacterial species. Disclosures Y. Yamano, SHIONOGI & CO., LTD.: Employee, Salary; R. Nakamura, SHIONOGI & CO., LTD.: Employee, Salary; T. Sato, SHIONOGI & CO., LTD.: Employee, Salary; M. Tsuji, Shionogi & Co.: Employee, Salary; R. Echols, Shionogi & CO., LTD: Consultant, Consulting fee

Impact of Carbapenem-Resistant Pathogens on Mortality among Hospitalized Adult Patients

Background: The spread of carbapenem-resistant (CR) Gram-negative bacteria has become a significant problem. We investigated the impact of CR Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli on all-cause in-hospital mortality. Methods: Hospitalized patients with laboratory confirmation of infection with each of four pathogens were identified in electronic health records from Premier Healthcare Database. Two cohorts (Resistant and Susceptible) were identified based on antibiotic susceptibility data. The primary outcome measured was all-cause in-hospital mortality. We investigated the impact of each pathogen on patients by each isolated site (Respiratory, Blood, Urine and Other). A logistic regression was used to analyze the association of in-house mortality and CR infection in all 16 bacteria/specimen site cohorts with and without adjusting for the following potential confounders: age, gender, race, Charlson comorbidity index, admission source, and admission type. Results: From 2009 to 2013, CR was identified in 44.8 % (2,916/6,508) of all A. baumannii infections; 14.1% (7,994/56,477) of all P. aeruginosa infections; 3.6% (2,025/56,552) of all K. pneumoniae; 0.2% (328/173,200) of all E. coli infections. In-hospital mortality was greater in most of the CR pathogens groups than Carbapenem Susceptible (CS) pathogens groups: especially for A. baumanni infection with blood stream isolate (crude OR = 3.91, 95% CI: 2.69-5.70). This effect remained after adjusting for the relevant confounders (adjusted OR=2.46, 95%CI: 1.43-4.22). In addition to CR, Mechanical Ventilation (all 16 models), Renal Impairment (9 models), Malignancy (11 models) and Mild liver disease (11 models) were also significantly associated with the in-hospital mortality with p-value <0.05. Conclusion: CR infections of A. baumannii and P. aeruginosa were more frequently detected in blood and respiratory sites. Patients with CR of A. baumannii blood infection had higher odds of in-hospital mortality, even after adjusting for potential confounders. These results highlighted the need of development of novel agents for CR infections. ABSTRACT